PROJECT 1 - ABSTRACT Age is the single greatest risk factor for Alzheimer's disease (AD); however, the mechanisms linking normative aging and AD remain obscure and have been understudied. The broader goals of this proposal are to (1) understand, at a molecular level, what processes cause cells to become more susceptible to AD as we age and (2) to leverage recent advances in aging research to develop novel therapies that will delay the onset and progression of AD in people. To begin to accomplish these goals, we will utilize the nematode Caenorhabditis elegans as a model system in order to understand the molecular and genetic basis of AD in the context of an aging animal. Specifically, we will develop improved transgenic nematode models for AD-related studies and use these models to accomplish two primary goals. First, we will determine the age-dependent effects of toxic amyloid-beta (A) on global mRNA expression through RNA-Seq analysis. These experiments will be designed and analyzed in a manner to optimally extract meaningful and relevant data that will provide the first comprehensive view of the impact of A on gene expression in the context of normative aging. Second, we will determine the mechanisms by which two important signaling pathways, the hypoxic response and the mechanistic target of rapamycin (mTOR), modulate cellular resistance to A toxicity. We have previously shown that both of these pathways regulate both normative aging and resistance to A in C. elegans. These studies are likely to provide novel insights into the relationship between normative aging and AD, as well as novel therapeutic targets to attenuate the onset and progression of AD in people.